The efficacy of conventional radioimmunotherapy in the treatment of human cancer is limited by inadequate localization of antibody in tumor and toxicity to marrow from circulating radioactivity. PRIT offers the advantages of (1) rapid, efficient, specific, and stable binding of tumor localized antibody receptor, and (2) rapid elimination of radioactivity from the whole body. We pretargeted epithelial tumors with a conjugate of a pancarcinoma-reactive monoclonal antibody (NR-LU-10) and streptavidin to act as a prelocalized, tumor-specific high affinity receptor. Forty-eight hours later the remaining circulating conjugate was cleared with biotinylated human serum albumin. Finally, 24 hours later radioactivity was delivered using a small molecule 90Y-DOTA-biotin ligand. After preliminary Phase I studies to optimize the doses and timing of the components of this PRIT regimen, 40 patients with refractory epithelial neoplasms (11 ovary, 10 colon, 9 prostrate, 6 breast, 4 misc.) were injected with increasing doses of 90Y. Dosimetry estimates for normal tissues and tumor were obtained. Of 33 patients currently evaluable for response, there were two partial responses (prostate and ovary), four minor responses (2 ovary, 1 colon, 1 prostate), and nine patients with stable disease. Toxicity has consisted of nausea and vomiting (Grade I/II, 20 pts.; Grade III/IV, 3 pts.); elevated liver function tests (Grade I/II, 16 pts.; Grade III/IV, 2 pts.); thrombocytopenia (Grade I/II, 9 pts.; Grade III/IV, 7pts.); Neutropenia (Grade I/II, 8 pts.; Grade III/IV, 4 pts.); and diarrhea (Grade I/II, 6 pts.; Grade III/IV, 4 pts.). The dose limiting toxicity of the PRIT was diarrhea at a dose level of 140 mCi/m2 90Y. Phase II trials of 90Y PRIT at 120 mCi/m2 are planned in patients with prostate, colon or small cell lung cancer.